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Title: Factors influencing the acute vascular inflammatory response in murine endotoxaemia
Author: Hughes, Ellen Lucy
ISNI:       0000 0004 2719 1601
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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The inflammatory response is a complex condition that can be visualised in terms of leukocyte activity at the microcirculatory level. Recent data show that leukocyte recruitment can be prevented by both the endogenous protein annexin A1 (AnxA1) and activation of its receptor FPR2/ALX (murine orthologue: Fpr2), thus aiding resolution of the inflammation. Furthermore, AnxA1 is sensitive to oestrogen (E2) and so is a candidate mediator of the sex differences seen in many inflammatory diseases. Using intravital microscopy to quantify leukocyte-endothelial cell interactions in the murine mesentery in real-time and in vivo, we aimed to establish a model of the systemic inflammatory response and determine the involvement of the AnxA1-Fpr2 system in effecting anti-inflammation. Lipopolysaccharide (LPS; 10 g/mouse I.P.) induced leukocyte rolling, adhesion and emigration, and plasma protein extravasation, observable at 2, 6 and 24 h after injection in mesenteric venules. At 2 h, leukocyte infiltration was also seen in the liver and plasma concentrations of TNF- , IL-6 and IL-10 were raised, indicating a systemic response. When given 20 min into, or at the end of, a 2 h LPS challenge, the Fpr2 ligands AnxA1Ac2-26 and LXA4 reduced LPS-induced adhesion, an effect that was blocked by both antagonists that were either pan-FPR (Boc2) or Fpr2-specific (WRW4). Our model also showed sexual dimorphisms, in that LPS-induced leukocyte-endothelial cell interactions and plasma TNF- and IL-10 concentrations were heightened in females. Ovariectomy revealed a particular role for ovarian hormones besides E2 in the manifestation of these differences, and the use of AnxA1-/- mice suggests that AnxA1 reduces the animals’ sensitivity to E2. These data suggest firstly that FPR2/ALX presents an attractive target for novel anti-inflammatory therapeutics, and secondly that ovarian function is important in the regulation of inflammation.
Supervisor: Gavins, Felicity ; Buckingham, Julia Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral